1. Field of the Invention
The present invention relates to the treatment of amyotrophic lateral sclerosis (ALS), the improvement of motor function and/or the prevention of a loss thereof in individuals in need of such improvement/prevention.
2. Description of the Background
Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease, affecting both the first and second motoneuron. The progression of ALS is characterized by a degeneration of motor neurons associated with a dramatic demyelination in the anterior horn of the spinal cord. The etiology is only partially understood. Of the 5-10% familial cases, 20% carry a mutation of the superoxide dismutase 1 (SODI) gene. Such a mutation is also present in 5% of the sporadic cases (Rowland New Engl J Med 2001:344:1688-1700).
Pathophysiologically, three major mechanisms are discussed in ALS: (a) mutations of the SODI gene, causing a toxic gain of function with enhanced reactivity towards abnormal substrates (tyrosine nitration), along with an impaired ability to bind zinc leading to a reduced antioxidant capacity; (b) mutations in neurofilament genes and oxidative modifications or hyperphosphorylation of cytoskeletal proteins leading to selective motor axon degeneration; (c) excitotoxicity caused by increased cerebrospinal fluid glutamate levels together with a loss of excitatory amino acid transporters (Rowland New Engl J Med 2001:344:1688-1700).
There is no promising treatment available to date. The only compound yielding borderline significance with respect to survival time is RILUZOLE® (2-amino-6-(trifluoromethoxy) benzothiazole), an antiexcitotoxin (Rowland New Engl J Med 2001:344:1688-1700). As the common basis of cellular and extracellular alterations in ALS seems to be oxidative stress mediated by reactive nitrogen/oxygen species, future attempts of treatment might focus on antioxidant strategies involving suppression of nitric oxide (NO) synthase.
Accordingly, there remains a prominent need for new therapies for improving or preventing the loss of motor function in such patients, such as ALS patients.
Melatonin and melatonin derivatives are known to obey and affect circadian rhythms in mammals when secreted from the pineal gland during the night (Reiter Prog Clin Biol Res 1981: 59C: 223-233; Stokkan & Reiter J Pineal Res 1994: 16: 33-36; Petrie et al., BMJ 1989: 298: 705-707). Based on these observations, melatonin is often used off the shelf for treating jet lag.
Melatonin is also well-known as an antioxidant in neuronal and non-neuronal tissues (J. Pineal Res. 1994: 17:94-100 and Life Sci 1994: 56:83-89). In fact, such antioxidant properties have been shown to rescue dopamine neurons from damage in an experimental model system (Iacovitti et al Brain Res 1997: Sep. 12: 768(1-2): 317-26, Melatonin rescues dopamine neurons from cell death in tissue culture models of oxidative stress). In addition, melatonin (at doses of 100 μM) has been shown to “counteract the in vitro destructive effects of NMDA or hypoxia/reperfusion by preventing accumulation of excessive free radicals” (Cazeville et al Brain Res 1997:768(1-2): 120-124). From these observations of the antioxidant properties of melatonin have been prescribed at 3 mg melatonin doses in the evening to ALSIMNI patients (Dr. Stanley Appel of the Baylor Clinic in Texas).
Melatonin and various melatonin derivatives have been described as being useful for treating anoxic or ischemic brain injury (U.S. Pat. No. 5,700,828).
However, melatonin has not been assessed for its effects when administered episodically at night in high doses in ALS patients or in patients with other related neurodegenerative disorders.